Stepan G Romanov

A novel synthesis of 3(R)-HETE, 3(R)-HTDE and enzymatic synthesis of 3(R), 15(S)-DiHETE

Abstract 3(R)-HETE and 3(R)-HTDE were prepared by cross-coupling of methyl 3(R)-hydroxyhex-5-ynoate either with 1-bromo-2,5,8-tetradecatriyne or 1-bromo-2-octyne followed by catalytic hydrogenation of the skipped triple bonds formed using Lindlars catalyst. Enzymatic synthesis of 3(R),15(S)-DiHETE was accomplished by soybean LOX-1 using 3(R)-HETE as a substrate.

A simple method for the preparation of (5Z,8Z,11Z,14Z)-16-Hydroxyeicosa-5,8,11,14-tetraenoic acid enantiomers and the corresponding 14,15-Dehydro analogues: role of the 16-Hydroxy group for the lipoxygenase reaction

(5Z,8Z,11Z,13E)-15-Hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) is not well oxygenated by arachidonate 15-lipoxygenases because of two structural reasons: (i) it contains a hydrophilic OH-group in close proximity to its methyl end and (ii) it lacks the bisallylic methylene at C(13). We synthesized racemic (5Z,8Z,11Z,14Z)-16-hydroxy-5,8,11,14-eicosatetraenoic acid (16-HETE) which still contains the bisallylic C(13), separated the enantiomers reaching an optical purity of >99% and tested them as substrates for 5- and 15-lipoxygenases. Our synthetic pathway, which is based on stereospecific hydrogenation of a polyacetylenic precursor, yielded substantial amounts (30%) of 14,15-dehydro-16-HETE in addition to 16-HETE. When 16-HETE was tested as lipoxygenase substrate, we found that it is well oxygenated by the soybean 15-lipoxygenase and by the recombinant human 5-lipoxygenase. Analysis of the reaction products suggested an arachidonic acid-like alignment at the active site of the two enzymes. In contrast, the product pattern of 16-HETE methyl ester oxygenation by the soybean lipoxygenase (5-lipoxygenation) may be explained by an inverse head to tail substrate orientation.

Total synthesis of (5Z,8Z,11Z,14Z)-18- and 19-oxoeicosa-5,8,11,14-tetraenoic acids

Abstract 18-oxo-ETE was synthesized via the corresponding tetraacetylenic precursor, which was prepared by cross-coupling of three key synthons: methyl 5-hexynoate, the bisfunctional C 7 –C 13 fragment—7-bromo-2,5-heptadiyne-1-ol and rac -3-(benzoyloxy)hept-6-yn. The carbonyl function was introduced at the last synthesis step. 19-oxo-ETE was synthesized by coupling of acid anhydride, prepared from monomethyl ester of (5 Z ,8 Z ,11 Z ,14 Z )-nonadeca-5,8,11,14-tetraen-1,19-dioic acid, either with lithium dimethylcuprate or methylcuprate in a one-step procedure.

18-Iodooctadeca-(8 Z ,11 Z )-dienoic Acid as Useful Intermediate for the Synthesis of Special Lipoxygenase Substrates Bearing Bulky Substituents at the ω-Position

18-Iodooctadeca-(8Z,11Z)-dienoic acid (7) was synthesized in five steps starting from methyl 10-bromodec-7-ynoate (2) in an overall yield of 53%. The synthetic procedure involves Cu(I)-catalyzed cross-coupling of propargylic bromide 2 with 7-octyn-1-ol (3), followed by hydrogenation of the coupling product 4 to Z,Z-diene 5 on Lindlars catalyst and subsequent substitution of the OH– group of 5 with iodine. Coupling of the resulting iodide 7 with low-order organic cuprates [t-Bu2CuLi or (PhCH2)2CuMgCl] leads to 19,19-dimethyleicosa-(8Z,11Z)-dienoic acid (1a) and 19-phenylnonadeca-(8Z,11Z)-dienoic acid (1b), respectively.